1,4-diaza-bicyclo(4,3,0)nonane-2,5,9-triones

ABSTRACT

NOVEL 1,4-DIAZA-BICYCLO (4,3,0) NONANE-2,5,9-TRIONES ARE OBTAINED BY TWO SYNTHETIC ROUTES. THE FIRST INVOLVES CYCLIZATION OF A-AMINOALKANOYL-GLUTAMIC ACIDS TO 3,6DIOXO-2-PIPERAZINE-PROPIONIC ACIDS WHICH UNDERGO A SECOND CYCLIZATION UPON REFLUXING WITH ACID ANHYDRIDE. IN THE SECOND ROUTE, COMPOUNDS OF THE NOVEL BICYCLIC SYSTEM WERE OBTAINED BY DIRECT CYCLIZATION OF N-ACETYL-AAMINOALKANOYL-GLUTAMIC ACID. THESE COMPOUNDS HAVE BEEN FOUND EFFECTIVE AS CENTRAL NERVOUS SYSTEM STIMULANTS AND DEPRESSANTS.

United States Patent Office 3,563,9921,4-DIAZA-BICYCLO[4,3,0]NONANE-2,5,9-TRIONES Michael R. Harnden,Waukegan, Ill., assignor to Abbott Laboratories, North Chicago, 11]., acorporation of Illinois N Drawing. Continuation-impart of applicationSer. No. 593,691, Nov. 14, 1966. This application Oct. 31, 1967, Ser.No. 679,524

Int. Cl. C0711 51/72 US. Cl. 260-268 9 Claims ABSTRACT OF THE DISCLOSURENovel 1,4-diaza-bicyclo [4,3,0] nonane-2,S,9-triones are obtained by twosynthetic routes. The first involves cyclization ofa-aminoalkanoyl-glutamic acids to 3,6- dioxo-Z-piperazine-propionicacids which undergo a second cyclization upon refluxing with acidanhydride. In the second route, compounds of the novel bicyclic systemwere obtained by direct cyclization of N-acetyl-aaminoalkanoyl-glutamicacid. These compounds have been found effective as central nervoussystem stimulants and depressants.

DESCRIPTION OF INVENTION This invention relates to certain novelcompositions of matter useful as substances for effecting a response inthe central nervous system, and is a continuation-inpart of applicationSer. No. 593,691 filed Nov. 14, 1966, now abandoned. More particularlythis invention pertains to 1,4-diaza-bicyclo [4,6,0]nonane-2,5,9-triones which exert depressant and stimulative effects inmammals.

This invention further involves methods for the preparation of thesecarbonyl compounds and certain intermediates prepared in the synthesisof such end products.

In its primary aspects, this invention therefore concerns a series orclass of novel 1,4-diaza-bicyclo [4,3,0] nonane-2,-5,9-triones thatgenerally maybe represented by the following structural formula:

0 O r H R.

N A I a wherein R represents hydrogen, methyl, ethyl, propyl, isopropyl,n-butyl, benzyl, monoloweralkoxybenzyl, diloweralkoxybenzyl,triloweralkoxybenzyl and 3,4-cyclomethylenedioxybenzyl; R representshydrogen, methyl, ethyl, propyl, isopropyl, and n butyl; and Rrepresents hydrogen and loweralkanoyl. In this specification the prefixlower preceding a term defining a functional group is intended to modifythe definition of that functional group to specifically include thosefunctional groups that have from 1-4 carbon atoms.

The compounds of the present invention can variously be prepared by twopreferred reaction methods, scheme A and scheme B. The first method,scheme' A, employs the following procedure.

3,563,992 Patented Feb. 16, 1971 An a-arninoalkanoyl-L-glutamic acid(Formula II) is heated to a temperature suflicient to cyclize the carbonof the carboxyl group with the nitrogen of the amino function, as shown,to form a 3,6-dioxo-2-piperazinepropionic acid (Formula III). Heating totemperatures of about -160 C. has by experience been shown to be quitesufiicient to induce reaction. The 3,6-dioxo-2- pipe'razine-propionicacid is then treated with a cyclizing agent such as trifluoraceticanhydride to form those compounds of this invention having R ==H(Formula I). This is done by creating a bond between the carbon of thecarboxyl group and the hydrogen of the amide group. The N-alkanoylderivatives, i.e. R ==alkanoyl, can be prepared by either refluxing thecompounds of Formula IV with an acid anhydride other thantrifiuoroacetic anhydride or by using such an acid anhydride as thecycliz-ing agent for the 3,6-dioxo-2-piperazinepropionic acids.

A second preparative scheme, scheme B, somewhat diiferent from scheme A,can also be used to prepare the novel compounds of this invention. Thereactive steps of this second procedure are as follows:

In reaction scheme B, the disodium salt of glutamic acid (Formula IV) isadded to an unsaturated azalaotone (Formula V), in which R representsbenzylidene, monoloweralkoxybenzylidene, diloweralkoxybenzylidene, tri--loweralkoxybenzylidene or 3,4-cyclomethylenedioxybenzylidene. Theaddition results in an oc-loweralkanoyl- Dose in mgJkg. body weightIntraper- R R R Oral itoneal Effect 0. 1-1, 000 0. 1-1, 000 Stimulant.

200-500 100-500 Depressant.

500 D0. 500-1, 000 200-1, 000 Do. 500-1, 000 500-1, 000 Do.

do. 200-500 Stimulant. Acetyl 500-1, 000 200-1, 000 Do. 0. 1-100 0. 1-10D0.

200 50 Depressant.

1, 000 500-1, 000 Do. 100-1, 000 100-1, 000 D0. Hydrogen 500-1, 000600-1, 000 Do. Hydrogen Beuzyl do 1,000 Do. Do Hydrogen 100-1, 00050-1,000 Do. Do "do 500-1, 000 100-1, 000 Do. Do d 200-1, 000 500-1, 000Do. Do 4-meth0xybeuzyl 100-1,000 Do. Do 3,4-dimethoxybenzyl. 200-1,000Do. Do. 3,4,5-trimeth0xybenz d0 100-1,000 Do.3,4-cyclomethylene-(lioxybenzyl "do 500-1, 000 200-1, 000 Do.

amidocinnamoyl-glutamic acid (Formula VI). The unsaturated bond betweenR, and the a carbonyl carbon is reduced by means such as reduction withhydrogen over a hydrogenation catalyst such as, for example, palladium.

This reduction yields the correspondingN-loweralkanoyl-a-amino-loweralkanoyl-glutamic acid (Formula VII) whichcan then be cyclized with an acid anhydride. R is a subclass of R andrepresents the benzyl, monoalkoxybenzyl, dialkoxybenzyl, trialkoxybenzylor cycloloweralkylenedioxybenzyl groups.

To those skilled in the art, it is apparent from the structure ofgeneric Formula I that there can exist stereoisomers of the compoundsrepresented by this formula. The individual stereoisomers and racemicmixtures can be made by varying the configuration, i.e., D or L or DL,of the starting material, and thus the configuration of the R and R onthe asymmetric carbon atom. Therefore, various stereoisomers and thecorresponding variety of racemic mixtures are included within the scopeof this invention.

The compounds of this invention can be prepared and administered in awide variety of oral and intraperitoneal dosage forms, eitherseparately, in combination, or admixed with other drugs. Thepharmaceutically active material may be associated with a carrier ifdesired, and the admixture of drug and carrier may comprise a solid; orbe a liquid solution, dispersion or suspension. The solid dosage formcan take the form of a tablet, a powder,

a capsule or the like, while the liquid dosage form can be a syrup, asuspension, an emulsion, an elixer, or the like. Those conventionalcarriers so well known in the art such as starch, sucrose, ethanol,glycerin and the like may thus be used.

Although the compounds of this invention can be administered in any ofthe stated physical forms with the stated carriers, the preferred formand carrier is a 1-3% by 'weight of aqueous suspension. When giventhusly, a small amount of tragacanth can be added to facilitateformation of a uniform suspension in those instances where suspension isotherwise difiicult to achieve. Sufiicient tragacanth to form a goodsuspension was found to comprise about 3% by weight of the liquid phase.

When administered by oral or intraperitoneal routes in dosages of arange from 0.1 to 1,000 mg./kg. body weight to laboratory animals, thosecompounds having either hydrogen or acetyl in the R position, and havingthe substituents in the R and R position, be either both hydrogen orethyl and methyl, show stimulative effects The following specificexamples are further illustrative of this invention, including aspectsof the compounds themselves, and methods of preparing them. Theseexamples are only for purposes of illustration and ought not beconstrued as an expressed or implied limitation upon the scope of theappended claims, and are not intended as limiting the concept of theinvention in any manner.

EXAMPLE I 1,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trioneGlycyl-L-glutamic acid was heated at a pressure of 1 mm. of mercury to atemperature of -160 C. for about 30 minutes. The resulting 3,6-dioxo-2piperazinepropionic acid (2.0 g.) was refluxed for one hour with 20 ml.of trifluoroacetic anhydride. The solution was then cooled andconcentrated at reduced pressure to a syrup that after treating with 10ml. ether gave a 1.86 g. of a pale yellow solid. This solid was thendissolved in 10 ml. ethanol and precipitated with 25 ml. ether. Thepurified product was then filtered and dried. It had a melting point of184-7 C., and a yield of 79% based upon the glycyl-L-glutamic acid. Theidentity of this product, as was the identity of the products of thefollowing examples was confirmed by elemental analysis and infra-red andNMR spectroscopy. The calculated values for a compound having theempirical formula C H N O are carbon 50.0%, hydrogen 4.8%, and nitrogen16.7%. Elemental analysis showed this product to contain 50.2%, 4.7%,16.8% respectively of these elements.

EXAMPLE II Levo-3-methyl-l,4-diaza-bicyclo [4,3,0] nonane- 2,5 ,9-trioneThe procedure was the same as in Example I, except the starting materialwas L-alanyl-L-glutamic acid and the recrystallization solvent wasethanol. The product was obtained in 72% yield and had a melting pointof 220-222 C. Analysis showed that the product contained 52.5% carbon,5.5% hydrogen and 15.4% nitrogen. The calculated values for C H N O are52.7%, 5.5% and 15.4% respectively.

EXAMPLE III 3-methyl-l,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trione Theprocedure was the same as in Example I, except the starting material wasDL-alanyl-L glutamic acid and the recrystallization solvent was ethanol.The product was obtained in 68% yield and had a melting point of 187-191C. and elemental analysis showed that the product contained 52.8%carbon, 5.4% hydrogen and 15.6% nitrogen. The calculated values for C HN O are 52.7%, 5.5% and 15.4% respectively.

EXAMPLE IV 3,3-dimethyl-1,4diaza-bicyclo[4,3,0]nonane-2,5,9-trione Theprocedure was the same as stated in Example I, except the startingmaterial was a-aminoisobutyryl-L- glutamic acid and therecrystallization solvent was ethanol-ether. The product was obtained in77% yield and had a melting point of 258-261" C. Elemental analysisshowed that the product contained 54.9% carbon, 6.5 hydrogen and 14.3%nitrogen. The calculated values for C H N O are 55.1%, 6.2%, and 14.3%respectively.

EXAMPLE V 3-iso-propy1-1,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trione Theprocedure was the same as in Example I, except the starting material wasDL-valyl-L-glutamic acid and the recrystallization solvent was ethanol.The product was obtained in 19% yield and had a melting point of190-220" C. Elemental analysis showed that the product contained 57.2%carbon, 6.7% hydrogen and 13.2% nitrogen. The calculated values for C HN O are 57.1%, 6.7%, and 13.3% respectively.

EXAMPLE VI Levo-3 -isobuty1-1,4-diaza-bicyclo [4,3 ,0] nonane-2,5,9trione The procedure was the same as in Example I, except the startingmaterial was L-leucyl- -glutarnic acid and the recrystallization solventwas ethanol. The product was obtained in 23% yield and had a meltingpoint of 215- 218 C. Elemental analysis shrowed that the productcontained 59.0% carbon, 7.2% hydrogen and 12.6% nitrogen. The calculatedvalues for C H N O- are 58.9%, 7.2% and 12.5% respectively.

EXAMPLE VII Levo-3-benzyl-1,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trioneThe procedure was the same as in Example I, except the starting materialwas L-phenylalanyl-L-glutamic acid and the recrystallization solvent wasa mixture of methanol and ether. The product was obtained in 57% yieldand had a melting point of 192-194 C. Elemental analysis showed that theproduct contained 64.8% carbon, 5.7% hydrogen and 11.0% nitrogen. Thecalculated values for C I-1 N 0 are 65.1%, 5.5 and 10.9% respectively.

EXAMPLE VIII Dextro-3-benzyl-1,4-diaza-bicyclo [4, 3,0] nonane-2,5,9-

trione The procedure was the same as in Example I, except the startingmaterial was D-phenylalanyl-L-glutamic acid and the recrystallizationsolvent was ethanol. The product was obtained in 69% yield and had amelting point of 196- 198" C. Elemental analysis showed that the productcontained 65.1% carbon, 5.4% hydrogen and 10.9% nitrogen. The calculatedvalues for C -H N O are 65.1%, 5.5 and 10.9% respectively.

EXAMPLE IX 3-ethyl-3-methyl-1,4-diaza-bicyclo[4,3,0] nonane-2,5,9-trione DL-isovalyl-L-glutamic acid was heated at a pressure of 1 mm. Hg.The resulting 3-ethyl-3-methyl-3,6-dioxo-2- piperazine propionic acid(2.0 g.) was refluxed for one hour with acetic anhydride. Afterrefluxing was completed the solution was cooled and concentrated atreduced pressure to a syrup, which a treatment with 10 ml. ether yielded(1.52 g.) of a buff colored solid. This solid was recrystallized fromacetone (15 ml.), and yielded 0.48 g.

(28% yield) of product having a melting point of 222- 5 C.

Analysis.--Calcd [for C H N O 57% carbon, 6.7% hydrogen and 13.3%nitrogen. Found: 57.2%; 6.6% and 13.1% respectively.

EXAMPLE X 3-ethyl-3-methyl-4-acety1-1,4-diaza-bicyclo[4,3,0]nonane- 2,5,9-trione The supernatant acetone solution from Example IX wasconcentrated at reduced pressure and 0.59 g. of a water insoluble solidobtained. This solid was washed with 15 ml. water, filtered and twiceagain washed. When dry, it gave a 26% (0.54 g.) yield to the producthaving a melting point 129131 C.

Analysis.-Calcd for C H N 0 57.1% carbon, 6.4% hydrogen, 11.1% nitrogen.Found: 57.4%, 6.5% and 11.2% respectively.

EXAMPLE XI 4-acetyl-1,4-diaza-bicyclo[4,3,0] nonane-2,5,9-trione Thiscompound was prepared in the same manner as Example I except aceticanhydride was substituted for trifluoroacetic anhydride. Reaction ofglycyl-L-glutamic acid gave a 78% yield of product having a meltingpoint of 148-150 C.

Analysis.Calcd for C H N O 51.4% carbon; 4.8% hydrogen and 13.3%nitrogen. Found: 51.7%, 4.9%, and 13.6% respectively.

EXAMPLE XII 3-methyl-4 acetyl-1,4-diaza-bicyclo[4,3,0] nonane-2,5,9-trione This compound was prepared in the same manner as Example IIexcept acetic anhydride was substituted for trifiuoroacetic anhydride.Reaction of L-alanyl-L-glutamic acid gave a 48% yield of product havinga melting point of 183-185 C.

Analysis.Calcd for C H N O 53.6% carbon, 5.4% hydrogen and 12.5%nitrogen. Found: 53.7%, 5.2%, and 12.7% respectively.

EXAMPLE XIII 3,3-dimethyl-4-acetyl-1,4-diaza-bicyclo[4,3,0] nonane- 2,5,9-trione This compound was prepared in the same manner as Example IVexcept acetic anhydride was substituted for trifluoroacetic anhydride.Reaction of a-amino-isobutyryl- L-glutamic acid gave a 47% yiel,d ofproduct having a melting point of 163-1-66 C.

Analysis.--Calcd for C H N O 55.5% carbon; 5.9% hydrogen and 11.8%nitrogen. Found: 55.6%, 6.2% and 11.7% respectively.

EXAMPLE XIV EXAMPLE XV 3-isobutyl-4-acetyl-1,4-diaza-bicyclo [4,3,0]nonane-2,5,9-

trione This compound was prepared in the same manner as Example VIexcept acetic anhydride was substituted for trifluoroacetic anhydride.Reaction of L-leucyl-L-glutamic acid gave a 32% yield of product havinga melting point of 158160 C.

Analysis.-Calcd for C H N O 58.6% carbon, 6.8% hydrogen and 10.5%nitrogen. Found: 58.6%, 6.9% and 10.5% respectively.

EXAMPLE XVI 3-benzyl-4-acetyl-l,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trione This compound was prepared in the same manner as ExampleVII except acetic anhydride was substituted for trifluoroaceticanhydride. Reaction of L-phenylalanyl-L- glutamic acid gave a 63% yieldof product having a melting point of 164l66 C.

Analysis.Calcd for C H N O 64.0% carbon, 5.4% hydrogen and 9.3%nitrogen. "Found: 64.1%, 5.4% and 9.5% respectively.

EXAMPLE XVII 4-propionyl-1,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trioneThis compound was prepared by the method set forth in Example Iexcepting that the intermediate 3,6-dioxo-2- piperazine-propionic acidwas refluxed with a 1:1 by volume mixture of dimethylformamide andpropionic anhydride. The product, in 66% yield, had a melting point of158-l60 C. after recrystallization from an ethanol-ether mixture. Theempirical formula for this product is C H N O and percentages calculatedfrom the formula are 53.6% carbon, 5.4% hydrogen and 12.5% nitrogen.Elemental analysis of the product showed it contained 53.9%, 5.7% and12.7% respectively of these elements.

EXAMPLE XVIII 4'butyryl-1,4-diaza-bicyclo [4,3,0] nonane-2,5,9-trioneThis compound was prepared as was the compound of Example XVII exceptthat a 1:1 by volume mixture of dimethylformamide and butyric anhydridewas refluxed with the 3,6-dioxo-2-piperazine-propionic acidintermediate. The product was obtained in 36% yield, and had a meltingpoint of 12l123 C. after recrystallization from an acetone-ethermixture. The empirical formula for this product is C H N O and thepercentages calculated from this formula are 55.5% carbon, 5.9%hydrogen, and 11.8% nitrogen. Elemental analysis of the product showedit contained 55.3%, 6.2% and 11.7% respectively of these elements.

EXAMPLE XIX 4-isobutyryl-1,4-diaza-bicyclo [4,3,0] nonane- 2,5,9-trioneEXAMPLE XX 3-(4-methoxybenzyl)-4-acetyl-1,4-diaza-bicyclo [4,3,0]nonane-2,5,9-trione This compound was prepared by stirring 600 ml. oflNNaOH into a 300 ml. acetone suspension of 44.1 g. L-glutamic acid.Shortly thereafter 65.2 g. 2-methyl-4- anisylidene-Z-oxazolin--one wasadded. After additional stirring for 3 hours all the oxazolin haddissolved, and the solution was acidified with 600 m1. lNHC Th l 8 tionwas then concentrated at reduced pressure to remove the acetone.Following overnight storage at 5 C. the crudea-acetamido-4-methoxycinnamoyl-L-glutamic acid was filtered andrecrystallized from isopropanol in a 74% yield having a melting point ofl89-191 C.

The ot-acetamido-4-methoxycinnamoyl-L-glutamic acid (50 g.) was thenhydrogenated in 250 ml. of glacial acetic acid at 60 C. and 2.7atmospheres pressure in the presence of 7.5 g. of a 5% palladium oncarbon catalyst. Reaction was judged to have been completed after onehour, but to insure completeness the hydrogenation was continued for anadditional hour. The catalyst was then removed by filtration and thefiltrate concentrated at reduced pressure. The last traces of aceticacid were removed from the white solidN-acetyl-DL-3-(4-methoxyphenyl)-alanyl-DL-glutamic acid at 50 C. and apressure of 1 mm. of mercury for 40 hours. This method was used toprepare the N-acyl-u-ammoacyl-glutamic acids in the following examples.

The N acetyl DL-3-(4-methoxyphenyl)-alanyl-DL- glutamic acid was thenrefluxed with 50 ml. acetic anhydride for one hour. The solution wasconcentrated at reduced pressure and a white solid obtained.Recrystallization from ethyl acetate-petroleum spirit mixture gave 55%yield of product having a melting point 168l69 C. The empirical formulais C17H1BN2O5, the calculated value being 61.8% carbon, 5.5% hydrogen,and 8.5% nitrogen. Elemental analysis showed the product to contain61.7%, 5.7% and 8.4% of these elements respectively.

'SteI'eOiSOmers of this product were obtained by also using the D and Lforms of the glutamic acid.

EXAMPLE XXI 3-benzyl-4-acetyl-1,4-diaza-bicyclo [4,3,0] nonane- 2,5,9-trione N-acetyl-DL-phenylalanyl-DL-glutamic acid was refluxed withacetic anhydride for one hour and recrystallization of the product froman ethyl acetate-petroleum spirit mixture gave a 49% yield having amelting point of 162164 C. The empirical formula is C H N O and bycalculation contains 64.0% carbon, 5.4% hydrogen, and 9.3% nitrogen.Elemental analysis of the product showed it contained 64.2%, 5.4%, 9.2%of those elements respectively.

EXAMPLE XXII 3- 3 ,4-dimethoxybenzyl) -4-acetyl-1,4-diaza-bicyclo[4,3,0] nonane-2,5,9-trione N-acetyl-DL-3,4-dimethoxyphenylalanyl-DL-glutamic acid was refluxed with acetic anhydride. Theresulting product, recrystallized from an ethyl acetate-petroleum spiritmixture was obtained in 42% yield having a melting point l72173 C. Theempirical formula is C H N O the calculated value being 60.0% carbon,5.6% hydrogen and 7.8% nitrogen. Elemental analysis showed the productcontained 60.2%, 5.7% and 7.8% of these elements respectively.

EXAMPLE XXIII 3- 3 ,4,5-trimethoxybenzyl)-4-acetyl-1,4-diaza-bicyclo[4,3,0] nonane-2,5,9-trione N acetylDL-3,4,5-trimethoxyphenylalanyl-DL-glutamic acid was refluxed withacetic anhydride. The resulting product, recrystallized from ethylacetate was obtained in a 40% yield having a melting point of 162- 164C. The empirical formula is C H N O the calculated value being 58.5%carbon, 5.7% hydrogen and 7.2% nitrogen. Elemental analysis showed theproduct contained 58.7%, 5.7% and 7.1% Of those elements respectively.

9 EXAMPLE XXIV3-(3,4-cyclomethylenedioxybenzyl)-4-acetyl-l,4-diazabicyclo [4,3,0]n0nane-2,5,9-trione wherein R is hydrogen methyl, ethyl, propyl,isopropyl, and n-butyl; R is hydrogen, methyl, ethyl, propyl, isopropyl,n-butyl, benzyl, monoloweralkoxy benzyl, diloweralkoxy benzyl,triloweralkoxy benzyl, and 3,4- cyclomethylene-dioxybenzyl, and R ishydrogen and loweralkanoyl.

2. A compound in accordance with claim 1 in which R R and R arehydrogen.

3. A compound in accordance with claim 1 in which R and R are hydrogenand R is loweralkanoyl.

4. A compound in accordance with claim 1 in which R and R are hydrogenand R is loweralkyl.

5. A compound in accordance with claim 1 in which R and R are hydrogen.

6. A compound according to claim 1 in which R is methyl, ethyl, propyl,isopropyl and n-butyl and R is hydrogen.

7. A compound according to claim 1 in which R is methyl, ethyl, propyl,isopropyl and n-butyl and R is loweralkanoyl.

8. A compound according to claim 1 in which R and R are hydrogen.

9. A compound according to claim 1 in which R is hydrogen and R is loweralkanoyl.

References Cited UNITED STATES PATENTS 3,227,719 1/1966 Hofmann 260-2683,317,524 5/1967 Freed 260268X 3,388,128 6/1968 Day 260268 FOREIGNPATENTS 19,431 10/1966 Japan.

DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,561,992 Dated Feb. 16, 197].

Inventor(s) Michael en It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 2, in Formula 111, the structural formula should appear as shownbelow instead of as shown in the patent Column 5, Example VI, line 7,the word "shrowed" should read --showed.

Column 6, Example XIII, line 6, the word "yiel,d" should read yield--.

Column 8, Example XXIII, line 7, the empirical formula should read as tad of 19 z2 2 ms 8 as shown in the patent.

Signed and sealed this 29th day of June 1971.

(SEAL) LAttest:

EDWARD M.FL2LTCH.ER,JR. WILLIAM E. SGHUYLER, JR. Attesting OfficerCommissioner of Patents

